The development of techniques for propagating T cell populations in vitro has been crucial to many of the recent advances in the understanding of T cell recognition of antigen and T cell activation. The development of culture methods for the generation of human antigen-specific T cell clones has been useful in defining antigens expressed by pathogens and tumors that are recognized by T cells to establish methods of immunotherapy to treat a variety of human diseases. Antigen-specific T cells can be expanded in vitro for use in adoptive cellular immunotherapy in which infusions of such T cells have been shown to have anti-tumor reactivity in a tumor-bearing host. Adoptive immunotherapy has also been used to treat viral infections in immunocompromised individuals.
Donor leukocyte infusions (DLI) in the allogeneic hematopoietic transplant setting can provide a clinically relevant boost of immunity to reduce opportunistic infections and to increase graft-versus-leukemia activity. Despite significant advances in applicability, DLI has not been available for single-unit recipients of unrelated cord blood transplant. Ex vivo expansion of cord blood T cells can be achieved with interleukin 2 (IL-2) and CD3/CD28 co-stimulatory beads. However, significant apoptosis occurs in proliferating T cells, diminishing the yield and skewing the CD4/CD8 ratio in the T-cell population, jeopardizing the potential efficacy of DLI.
Lymphopenia is one consequence of hematopoietic cell transplantation. DLI may be used to treat lymphopenia by transferring naturally primed and typically resting, unmanipulated leukocytes. T lymphocytes represent a fraction of the total leukocytes present in blood, ranging typically between 20-30%. To correct T cell lymphopenia, however, more cells are needed than is available. Once cord blood grafts are thawed and the majority infused, there is insufficient numbers available. Besides the numerical shortage, T lymphocytes present in cord blood are also antigen inexperienced and functionally impaired/hyporesponsive, rendering them less suitable for treating infections.
Accordingly, alternative methods for expanding T cell populations, such as from cord blood, which lack alloreactivity against a host or host's cells, and methods for generating antigen-specific cytotoxic T cells from expanded T cell populations would be beneficial.